Disclaimer: This article is intended solely for informational and educational purposes only. It does not constitute medical advice.

Nitrous oxide (N2O), also known colloquially as “laughing gas,” was first synthesized by Joseph Priestly, an English chemist, in 1772, well before the discovery of anesthesia itself.1 Centuries later, it is widely used medically for its rapid-onset and short-duration analgesic and anesthetic effects. N2O is stable and chemically inert; it is a bacteriostatic gas that leaves no taste or odor. It is commonly used in the culinary, car racing, and oil industries for whipped cream pressurization, speeding combustion, and tracing leaks, respectively. The gas also has a long history of recreational use, which dates to the “laughing gas parties” of the Victorian era.2 Although the physiological effects that make nitrous oxide useful in clinical settings drive its recreational use, they also introduce the same clinical risks into non-clinical, unmonitored settings. 

Since the 2010s, recreational N2O usage has increased, particularly among young adults and in nightlife and festival settings. The drug, which is typically inhaled through balloons, can be used to produce a euphoric, pleasant, joyful, empathogenic, and sometimes hallucinogenic effect that is rapidly induced and disappears soon after. Despite its widespread availability, low cost, and perceived safety, recreational nitrous oxide carries risks such as dizziness, impaired coordination, loss of consciousness, and in more serious cases, hematological and neurological complications.2  

The mechanisms underlying nitrous oxide’s effects are not fully understood, but its anesthetic and psychoactive effects are known to involve several neurotransmitter systems, including dopamine, α2-adrenergic, GABA, and NMDA. When N2O inhibits NMDA receptors, excitatory glutamatergic signaling in the brain is reduced. The drug’s analgesic effects result from the release of endogenous opioids in the brainstem, which stimulates descending noradrenergic neurons to inhibit pain processing in the spinal cord.3 Like ketamine, the euphoric and hallucinogenic effects of N2O arise from NMDA receptor inhibition. 

In most countries, N2O is not classified as an illicit substance, so it is not consistently monitored in typical drug use surveys. More recently, increasing prevalence of recreational N2O has been reported in the Western world.4 Between 2016 and 2018, recreational use of the drug in the Netherlands increased from 11.0% to 17.6% among adolescents aged 18–19 and 20.8% to 25.2% among young adults aged 20–24. From 2010–2015, there were only 6 reported poisonings from N2O; however, that number increased to 144 by 2020.5 In Australia, past 6-month usage among young frequent drug users increased from 23% in 2014 to 67% in 2020. Emergency room admittance also increased fivefold from 2016 to 2018.6 In the Western world, reports found that N2O usage was especially high among young non-Western immigrants. 

While most recreational users do not experience severe health effects, N2O can induce serious health risks when used for prolonged periods of time or in high doses. A systematic review of 92 case studies found neurological consequences were reported in 77 cases, including myeloneuropathy (33%), sub-acute combined degeneration (18%), peripheral neuropathy or polyneuropathy (16%), and myelopathy (15%).7 N2O abuse has also been reported to cause frostbite and pulmonary toxicity. In 11 of the 92 cases, psychiatric problems, such as delusion or delirium, were described. Additionally, irritability, psychotic problems, self-harm, and violent behaviors have been recorded following recreational nitrous oxide use.4  

In the Netherlands, 64 adolescents were hospitalized from 2018 to 2020 and subsequently diagnosed with paraplegia. In severe cases, the patients remained permanently dependent on wheelchairs.4 Since 2019, 1,800 N2O-related traffic accidents were reported by the Dutch national police; 63 were fatal, while 362 involved serious injury. Of the drivers, 47% were entirely unaware that N2O would seriously impair their driving.4 While N2O is known for its fast elimination, residual subjective effects have been observed 15 minutes post-inhalation, presenting a potential cause for traffic accidents.8   

Nitrous oxide is widely accessible and often perceived as a relatively harmless recreational drug. However, growing evidence demonstrates that heavy or frequent use can result in serious neurological, psychiatric, and other physiological complications. Increasing recreational nitrous oxide use among young adults highlights the need for greater awareness of its risks and continued monitoring of its growing usage. 

References 

1. Gillman MA. Mini-Review: A Brief History of Nitrous Oxide (N2O) Use in Neuropsychiatry. Current Drug Research Reviews; 2019;11(1):12-20. 10.2174/1874473711666181008163107 
2. van Amsterdam J, Nabben T, van den Brink W. Recreational Nitrous Oxide Use: Prevalence and Risks. Regulatory Toxicology and Pharmacology; 2015;73(3):790-796. 10.1016/j.yrtph.2015.10.017  
3. Ohashi Y, Guo T, Orii R, Maze M, Fujinaga M. Brain Stem Opioidergic and GABAergic Neurons Mediate the Antinociceptive Effect of Nitrous Oxide in Fischer Rats. Anesthesiology; 2003;99(4):947-954. doi:10.1097/00000542-200310000-00030 
4. van Amsterdam JG, Nabben T, van den Brink W. Increasing Recreational Nitrous Oxide Use: Should We Worry? A narrative review. Journal of Psychopharmacology; 2022;36(8):026988112210824. 10.1177/02698811221082442 
5. van Riel AJHP, Hunault CC, van den Hengel-Koot IS, Nugteren-van Lonkhuyzen JJ, de Lange DW, Hondebrink L. Alarming increase in poisonings from recreational nitrous oxide use after a change in EU-legislation, inquiries to the Dutch Poisons Information Center. International Journal of Drug Policy; 2022;100:103519. 10.1016/j.drugpo.2021.103519 
6. Karlsson A, Peacock A, Sutherland R. South Australian Drug Trends 2024: Key Findings from the Ecstasy and Related Drugs Reporting System (EDRS) Interviews. Unsweduau; Published online December 5, 2024. 10.26190/unsworks/30690 
7. Garakani A, Jaffe RJ, Savla D, et al. Neurologic, Psychiatric, and Other Medical Manifestations of Nitrous Oxide Abuse: A Systematic Review of the Case Literature. The American Journal on Addictions; 2016;25(5):358-369. 10.1111/ajad.12372 
8. Kamboj SK, Zhao H, Luzia Troebinger, et al. Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers. International Journal of Neuropsychopharmacology2021;24(7):551-561. 10.1093/ijnp/pyab009